Several naturally-occurring alkaloids obtainable from Vinca rosea have been found active in the treatment of experimental malignancies in animals. Among these are leurosine (U.S. Pat. No. 3,370,057), vincaleukoblastine (vinblastine) to be referred to hereinafter as VLB (U.S. Pat. No. 3,097,137), leurosidine (vinrosidine) and leurocristine (VCR or vincristine) (both in U.S. Pat. No. 3,205,220), deoxy VLB "A" and "B", Tetrahedron Letters, 783 (1968) (desacetyl leurosine hydrazide is also disclosed therein); 4-desacetoxy vinblastine (U.S. Pat. No. 3,954,773); 4-desacetoxy-3'-hydroxyvinblastine (U.S. Pat. No. 3,944,554); leurocolombine (U.S. Pat. No. 3,890,325), leuroformine (N-formylleurosine), see Belgian Pat. No. 811,110) and vincadioline (U.S. Pat. No. 3,887,565). Two of these alkaloids, VLB and vincristine, are now marketed as drugs for the treatment of malignancies in humans, particularly the leukemias and related diseases.
The more abundant dimeric indole-dihydroindole alkaloids obtainable from Vinca rosea can be represented by the formula: ##STR1##
In the above formula where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, VLB is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxyl and R.sup.5 is H, leurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 and R.sup.5 are H and R.sup.4 is ethyl, deoxy VLB "A" is represented; where R.sup.1, R.sup.2 and R.sup.5 are the same as in deoxy VLB "A" but R.sup.3 is ethyl and R.sup.4 is hydrogen, deoxy VLB "B" is represented; and where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together form an .alpha.-epoxide ring, leurosine is represented.
Leuroformine has the same structure as leurosine except that R.sup.2 is formyl, not methyl. Leurocolombine and vincadioline are 2'-hydroxy VLB and 3'-hydroxy VLB respectively; 4-desacetoxy VLB has the same structure as VLB except that R.sup.1 is H rather than acetoxy; and 3'-hydroxy-4-desacetoxy VLB could also be called 4-desacetoxy vincadioline.
Chemical modification of the Vinca alkaloids has been rather limited. In the first place, the molecular structures involved are extremely complex and chemical reactions which affect only one specific function of the molecule are difficult to develop. Secondly, alkaloids lacking desirable chemotherapeutic properties have been recovered from Vinca rosea fractions, and a determination of their structures has led to the conclusion that these compounds are closely related to the active alkaloids. Thus, anti-neoplastic activity seems to be limited to very specific structures, and the chances of obtaining more active drugs by modification of these structures would seem to be correspondingly slight. Among the successful modifications of physiologically-active alkaloids has been the preparation of dihydro VLB (U.S. Pat. No. 3,352,868) and the replacement of the acetyl group at C-4 (carbon no. 4 of the VLB ring system--see the numbered structure above) with higher alkanoyl groups or with unrelated acyl groups. (See U.S. Pat. No. 3,392,173.) Several of these derivatives are capable of prolonging the life of mice inoculated with P1534 leukemia. One of the derivatives in which a chloracetyl group replaced the C-4 acetyl group of VLB was also a useful intermediate for the preparation of structurally modified VLB compounds in which for example an N,N-dialkylglycyl group replaced the C-4 acetyl group of VLB (see U.S. Pat. No. 3,387,001). An intermediate compound, namely 4-desacetyl VLB, was produced during the chemical reactions leading to these latter derivatives. This intermediate, in which the C-4 acyl group was lacking, leaving an unesterified hydroxyl group, was reported to be a toxic material having little in vivo chemotherapeutic activity against the P1534 murine leukemia system by Hargrove, Lloydia, 27, 340 (1964). More recent work, however, has shown 4-desacetyl VLB to be an active anti-tumor agent--see Owellen Fed. Proc. 34, 808 (1975) and Cullinan et. al., 9th International Congress of Chemotherapy, London, 1975, Abstract SC-19.
One of the more recent, and successful, chemical modifications of the dimeric indole-dihydroindole alkaloids from vinca has been the replacement of the C-3 ester function with an amide or hydrazide function usually with the concomitant loss of the acetyl at C-4 (which group can be replaced). Amides of the alkaloids VLB, leurosidine, vincristine, deoxy VLB "A" and "B", leurocolombine, vincadioline, 4-desacetoxy VLB, 3'-hydroxy-4-desacetoxy VLB, etc. are disclosed in Belgian Pat. No. 837,390.
Two of the above alkaloids, VLB and vincristine, are now marketed for the treatment of malignancies in humans and two others, leuroformine and 4-desacetyl VLB C-3 carboxamide (vindesine) are now on clinical trial in Europe or the United States as potential "anti-cancer" drugs.
It is an object of this invention to convert the relatively abundant alkaloid leurosine to structures having greater antimitotic action.